It is projected that 500,000 people will die from cancer, and that another 1,500,000 will be diagnosed with the disease in 2008. Consequently there is a huge unmet medical need for new anti-cancer drugs. This study will focus on developing drugs against fatty acid synthase (FAS), the sole enzyme in humans that converts dietary carbohydrate to fat. FAS has only marginal importance in adults, but its activity is essential for the proliferation and survival of most tumor cells. FAS is up-regulated in all the major solid tumors, and in most cases its expression is indicative of poor prognosis. There is an overwhelming body of evidence underscoring the functional significance of FAS to tumor growth and survival, and evidence that its pharmacological inhibition can prevent tumor growth in vivo. However, no study has addressed the most important issue relevant to translating this information into the improvement of human health: can a drug-like small molecule inhibitor of FAS be developed that can be advanced into pre-clinical development? The long-term objective of this study is to address this major issue through the following Specific Aims: 1) Design and synthesize potent, selective and reversible small molecule inhibitors of the thioesterase domain of FAS. These inhibitors will be based on hits obtained from screening libraries of drug-like compounds, and on structural insights into the enzyme. 2) Evaluate the potency and selectivity of compounds synthesized in Aim 1; the FAS inhibitors will be assessed for (a) potency in assays measuring the catalytic activity of the recombinant thioesterase and the purified FAS holoenzyme, (b) for off-target effects against other human thioesterases, (c) cytotoxic potency against lipogenic and non-lipogenic tumor cells, (d) physicochemical and ADME/T properties using standard in vitro assays. 3) Evaluate the novel inhibitors of FAS for anti-tumor activity. The compounds will be evaluated for the ability to reduce tumor growth in mouse xenograft models of human breast and prostate cancer. The intent of this project is to deliver a drug-like compound with nanomolar affinity for FAS that exhibits anti- tumor activity in vivo, with a reasonable therapeutic index. PUBLIC HEALTH RELEVANCE: This study focuses on developing anti-cancer drugs against fatty acid synthase (FAS), an enzyme that converts dietary carbohydrate to fat and that has only marginal importance in adults, but whose activity is essential for the proliferation and survival of most tumor cells. FAS is up-regulated in all the major solid tumors, and in most cases its expression is indicative of poor prognosis. The intent of this project is to develop a drug-like compound with nanomolar affinity for FAS that exhibits anti-tumor activity in vivo with a reasonable therapeutic index.